5,6-Diaryl-1,2,4-triazines are known as anti-inflammatory and antithrombotic agents. Such triazines can be represented by the following structural formula. ##STR1##
For example, U.S. Pat. No. 3,948,894 discloses a group of 5,6-diaryl-1,2,4-triazines according to formula I in which R is amino, such as dialkylamino, 4-(2-hydroxyethyl)piperazino, 4-hydroxypiperidino, piperidino, .alpha.-pipecolino, pyrrolidino, alkylamino, 2-hydroxyethylamino or bis(2-hydroxyethyl)amino and R.sup.1 and R.sup.2 are, independently, alkoxy, dimethylamino, F or methylsulfinyl. The compounds are said to be anti-inflammatory agents. A divisional application covering compounds in which R is morpholino issued as U.S. Pat. No. 4,008,232, and an earlier divisional application covering a method of treating inflammation with the same group of compounds issued as U.S. Pat. No. 3,979,516. In U.S. Pat. No. 3,989,831, the corresponding 3-chloro derivatives (R is Cl) are claimed as is a method of treating inflammation topically. Topical pharmaceutical formulations useful in the treatment method are also claimed in U.S. Pat. No. 3,989,831.
5,6-Diaryl-1,2,4-triazines in which R is XR.sup.3, X is O, S or a direct bond and R.sup.3 is alkyl or aralkyl, cycloalkyl or cycloalkylalkyl and R.sup.1 and R.sup.2 are independently halo, alkyl, alkoxy or dialkylamino are claimed in U.S. Pat. No. 4,013,654. These compounds are stated to be topically-active anti-inflammatory agents. This therapeutic use is claimed separately in U.S. Pat. Nos. 4,018,923 and 4,021,553. Ho and coworkers delineated the anti-inflammatory activity of the 5,6-diaryl-1,2,4-triazines and their high degree of effectiveness as inhibitors of fatty acid cyclooxygenase (50-100 times indomethacin) in a paper presented at the spring 1979 meeting of The American Chemical Society, Medicinal Chemistry Section, Abstract 059.
Some anti-inflammatory agents are known to have antithrombotic activity--see J. B. Smith, page 229 et seq of Prostaglandin Synthetase Inhibitors--Editors, H. J. Robinson and J. R. Vane (Raven Press, N.Y. 1974). Applicant knows of no instance where an antithrombotic effect was achieved by topical application of the drug.
In approaching the medical problems involved, in the prevention of thrombosis and particularly in studying the effect of inhibiting platelet aggregation in thrombus formation, some background information might be useful.
A thrombus generally is defined as a plug or clot in a blood vessel or in one of the cavities of the heart, with said plug or clot remaining at the point of formation. When a thrombus is either free-floating in the blood stream or has been removed by the blood stream to a new location, it is referred to as an embolus. These two entities are responsible for a variety of disorders which are generally termed thromboembolic diseases. Such diseases include phlebothrombosis, thrombophlebitis, pulmonary embolism, retinal thrombosis, myocardial infarction, and cerebral infarction.
The chemoprophylactic or chemotherapeutic management of thromboembolic diseases generally involves compounds which fall into one of three categories: (1) platelet aggregation inhibitors, (2) anticoagulants, and (3) fibrinolytic agents. The chemotherapeutic use of fibrinolytic agents is based upon the fact that fibrin frequently forms the primary structural support of a clot. Dissolution of the fibrin should result in lysis of the clot with restoration of blood flow. Thus, thrombi in place can be treated. Anti-coagulants and platelet aggregation inhibitors, on the other hand, generally are employed prophylactically. Anticoagulants are more effective in the treatment of venous thrombosis than arterial thrombosis because of slower blood flow on the venous side which permits coagulation factors, not platelets, to play an important role. While anti-coagulants might not prevent the formation of a platelet-dominated thrombus in the arterial circulation, they can inhibit the stabilization and extension of that thrombosis. However, the successful prophylaxis of arterial thrombosis must deal with the etiologic role of the platelet. The value of platelet function inhibitors in venous thrombosis will be reflected by the extent to which platelets are involved in the formation of those thrombi. Certainly, within the circulatory system, there are regions of stasis in which fibrin formation would be virtually the sole participant in thrombosis, but there would be other regions of high hemodynamic activity where the platelet nidus alone could block the vessel. Between these two extremes, there are situations in which fibrin formation and platelet aggregation occur more or less simultaneously, each supporting the other.
It is an object of this invention to provide platelet aggregation inhibitors which manifest an anti-thrombotic effect when administered topically.